Protection of COVID-19 Vaccination Against Hospitalization During the Era of Omicron BA.4 and BA.5 Predominance: A Nationwide Case–Control Study Based on the French National Health Data System

Abstract Background Knowing the duration of effectiveness of coronavirus disease 2019 (COVID-19) booster doses is essential to providing decision-makers with scientific arguments about the frequency of subsequent injections. We estimated the level of protection against COVID-19-related hospitalizations (Omicron BA.4-BA.5) over time after vaccination, accounting for breakthrough infections. Methods In this nationwide case–control study, all cases of hospitalizations for COVID-19 identified in the comprehensive French National Health Data System between June 1, 2022, and October 15, 2022, were matched with up to 10 controls by year of birth, sex, department, and an individual COVID-19 hospitalization risk score. Conditional logistic regressions were used to estimate the level of protection against COVID-19-related hospitalizations conferred by primary and booster vaccination, accounting for history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Results A total of 38 839 cases were matched to 377 653 controls; 19.2% and 9.9% were unvaccinated, respectively, while 68.2% and 77.7% had received ≥1 booster dose. Protection provided by primary vaccination reached 45% (95% CI, 42%–47%). The incremental effectiveness of booster doses ranged from 69% (95% CI, 67%–71%; ≤2 months) to 22% (95% CI, 19%–25%; ≥6 months). Specifically, the second booster provided an additional protection compared with the first ranging from 61% (95% CI, 59%–64%; ≤2 months) to 7% (95% CI, 2%–13%; ≥4 months). Previous SARS-CoV-2 infection conferred a strong, long-lasting protection (51% ≥20 months). There was no incremental effectiveness of a second booster among individuals infected since the first booster. Conclusions In the era of Omicron BA.4 and BA.5 predominance, primary vaccination still conferred protection against COVID-19 hospitalization, while booster doses provided an additional time-limited protection. The second booster had no additional protection in case of infection since the first booster.

Mass vaccination resulted in a significant decrease in hospitalizations and mortality from coronavirus disease 2019 (COVID-19) [1][2][3][4].However, an upsurge of severe COVID-19 has been observed in vaccinated populations and might be linked to a decline in vaccine effectiveness over time [5] and/or the emergence of new variants.Since mid-June 2022, the Omicron BA.4 and BA.5 subvariants have become the predominant strains circulating in France [6].This prompted authorities to recommend a first booster dose with the mRNA vaccines, which was rapidly expanded to all adults on November 27, 2021.A second booster dose was recommended in March 2022 [7], initially limited to the oldest individuals and then offered in July 2022 to individuals at risk for a severe form of the disease [8,9].In June 2022, ∼60% of the French population had received at least 1 booster dose, with little evolution since [10].
While a large part of the world's population has now acquired some form of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [11], either through previous infection or vaccination, the question of the durability of the protection over time remains crucial to mitigate the impact of the disease.In a recent systematic review [12], protection against severe disease was maintained at a relatively high Open Forum Infectious Diseases M A J O R A R T I C L E level up to 1 year after infection.In a previous study [13], we estimated that the effectiveness of the first booster against hospitalization for COVID-19 reached 83% and then decreased to 78% after 4 months.However, this study did not consider the second booster, did not cover the currently circulating Omicron BA.4 and BA.5 subvariants, and did not consider the interplay between prior SARS-CoV-2 infection and vaccination in maintaining protection.
Here, our objective was to estimate the level of protection against hospitalization for COVID-19 (Omicron BA.4 and BA.5) over time after vaccination, accounting for breakthrough infections.

Data Sources
This matched case-control study used data from the national COVID-19 vaccination database (VAC-SI: vaccine products and injection dates), coupled with the SARS-CoV-2 diagnosis testing database (SI-DEP: information on positive tests by reverse transcription polymerase chain reaction or antigenic tests) and with the National Health Data System (SNDS), which covers the entire French population (67 million residents).Each person is anonymously identified by a unique, lifelong number.Since 2006, the SNDS has recorded all reimbursement data for outpatient care, including drugs, imaging, and laboratory tests; inpatient care (including diagnoses and procedures performed) from the national hospital discharge database (Programme de Médicalisation des Systèmes d'Information [PMSI]); and health expenditure for patients with long-term diseases, such as cancer and diabetes, which are fully reimbursed in France.Information on hospital stays is collected monthly in the PMSI, and since July 2020, all COVID-19-related hospital stays have been reported through a fast-track procedure.Our study was based on data from this fast-track PMSI database available as of December 9, 2022, with data completeness of about 40% for October.The SNDS has been extensively used to conduct real-life pharmacoepidemiological studies, including on the COVID-19 pandemic [1,2,[14][15][16].

End Point, Design, and Study Population
The primary outcome was hospital admissions with a principal or related diagnosis of COVID-19 [1].Cases of COVID-19 diagnosis during a hospitalization for another reason (associated diagnosis) were not included.In this case-control study, cases were all individuals aged 12 years or over admitted to the hospital for COVID-19 between June 1, 2022, and October 15, 2022.If several hospitalizations occurred during this period, the first was considered.It should be noted that only very rare cases of re-hospitalization occurred during this period.Because our study related to the Omicron BA.4 and BA.5 variants, we included patients hospitalized for COVID-19 with no history of hospitalization for COVID-19 in the past 3 months [17].To identify controls at similar risk for severe COVID-19, we constructed an individual risk score [18] for COVID-19 hospitalization based on previous reported associations [19] from a Cox proportional hazards model between the risk of hospitalization for COVID-19 and ∼50 medical conditions plus sociodemographic characteristics, measured in 28 million individuals with a complete primary vaccination in 2021 (details of selected pathologies are given in Table 1).The risk score was calculated as the sum of each identified risk factor (pathologies and sociodemographic characteristics) weighted by the association coefficient obtained by the multivariable Cox model.This score was calculated for the nearly 60 million French residents aged 12 years and older, not deceased as of June 1, 2022, and with at least 1 health care expenditure in 2021.It was discretized into 20 classes based on the quantiles of distribution among the cases included.Each case of hospitalization was then matched on the date of hospital admission (index date) by year of birth, sex, department, and COVID-19 hospitalization risk score class with up to 10 controls without a history of hospitalization for COVID-19 in the past 3 months at the index date.For all matched individuals (each case and its controls), the index date corresponds to the date of hospital admission of the case.

Exposure
We defined vaccination status at the index date by identifying the date and number of injections administered.As the effectiveness of vaccines requires a delay from injection, we only considered administration of injections at least 14 days before the index date.Injections administered within 14 days before the index date were not counted and were therefore considered not administered, as they were not effective yet.The number of doses received and the exposure windows, depending on the interval between the last dosage and the index date, were used to establish vaccination status: 14 days-2 months; 2-4 months; 4-6 months; 6-9 months; ≥9 months.We specifically estimated the effectiveness of the first and second booster doses (the third booster dose affecting only 0.2% of our study population) overall and according to the time since last dose: 14 days-2 months; 2-4 months; ≥4 months.More detailed information on the type of COVID-19 vaccines used in France, as well as on the circulation of variants, is available in the eMethod section in the Supplementary Data.

Sociodemographic Characteristics and Chronic Diseases
Sociodemographic variables included age, gender, and region of residence.Age was divided into subgroups of 12-34-year-olds, 35-44-year-olds, 45-54-year-olds, and 5-year age groups for those 55 and older.We considered the social deprivation index as an estimation of socioeconomic status.This indicator, at the level of city of residence, has been extensively used and is based on the median household income, percentage of high school graduates in the population over the age of 15, percentage of manual workers in the labor force, and unemployment rate [20].We defined comorbidities using the Cartographie des Pathologies et des Dépenses, a tool developed from the SNDS and PMSI databases that allows the identification of diseases in a given year through medical algorithms [21] based on the reasons for hospitalization, LTD diagnoses, and/or reimbursement of specific treatments in the previous 4 years.This mapping of diseases and expenditures allowed the identification of patients presenting with 42 of these comorbidities in 2021 (cardiometabolic, respiratory, inflammatory, neurodegenerative diseases, cancer, mental and behavioral disorders, etc.) and was completed by the identification of obese patients, people with Down syndrome, psoriasis, heart, lung, or liver transplant recipients, smokers, alcohol or opioid use disorders, and patients treated with immunosuppressants or oral corticosteroids [19].
History of SARS-CoV-2 infection was identified from positive polymerase chain reaction and antigenic tests and hospitalizations for COVID-19 (excluding, for cases and controls, positive tests <2 months before the index date [22] and hospitalizations <3 months before the index date as possible markers of ongoing infection at the index date).

Statistical Analysis
Crude associations and multivariable conditional logistic regression models, adjusting for the risk factors that were more common and most strongly associated with odds of hospitalization for severe COVID-19 (ie, deprivation index, tobacco use, immunosuppressive treatment, diabetes, dyslipidemia, hypertensive treatments, chronic respiratory diseases, and other cancers before the index date) were used to estimate protection against hospitalization for COVID-19 after vaccination or prior infection.Multivariable models were also adjusted for the number of doses when estimating protection after a previous infection and for history of SARS-CoV-2 infection when estimating protection after booster vaccination.
Effectiveness was calculated as (1 -odd ratio [OR]) × 100, with the lower and upper limits of the confidence interval calculated as (1 − OR Upper ) × 100 and (1 − OR Lower ) × 100, respectively.
The effectiveness of vaccination on the risk of hospitalization for COVID-19 was estimated by considering as reference vaccination status: (i) no vaccination; (ii) a complete primary vaccination (2 doses); (iii) for the second booster dose, a complete primary vaccination followed by a first booster dose.
When estimating the second booster's effectiveness, we also performed stratified analyses according to history of infection after the first booster dose (later referred to as a recent infection).We estimated the effectiveness of hybrid immunity (ie, the combined effectiveness of the second booster dose and a recent infection) relative to those with a first booster dose but without a second booster dose or a recent infection.

Regulatory Approval and Ethical Aspects
The National Health Data System is a set of strictly anonymous databases comprising all mandatory national health insurance reimbursement data, particularly data derived from the processing of health care claims (electronic or paper claims) and data from health care facilities (PMSI).
EPI-PHARE has direct access to the SNDS from the permanent regulatory access of its constitutive bodies, the French National Agency for the Safety of Medicines (ANSM) and Health Products and the French National Health Insurance (Cnam).This permanent access is given according to the French Decree No. 2016-1871 of December 26, 2016, relating to the processing of personal data called the "National Health Data System" [23] and French law articles Art.R. 1461-13 [24] and 14 [25].This study was declared before its initiation on the EPI-PHARE registry of studies requiring the SNDS.

RESULTS
Between June 1 and 15 October 2022, 39 059 individuals were hospitalized for COVID-19.Among them, 38 839 (>99%) were matched to 377 653 nonhospitalized controls with the same year of birth, sex, area of residence, and COVID-19 hospitalization risk score range (Figure 1).Characteristics of the cases and their controls are presented in Table 1.Cases and controls were, on average, 75 years old; 51% were men and were comparable in medical history, including 24% vs 25% with diabetes, respectively, and 19% with chronic respiratory disease, 65% with hypertension, and 1.5% with lung cancer in both groups.

Table 2. Effectiveness of Vaccine Boosters on the Risk of Hospitalization for COVID-19 During the Omicron Period According to the Number of Doses Received or the Time Since the Last Dose
Booster doses conferred an estimated 32% (95% CI, 30%-35%) protection against the risk of hospitalization for COVID-19 compared with primary vaccination (Table 2).This protection ranged from 69% (95% CI, 67%-71%) in the first 2 months after to 22% (95% CI, 19%-25%) beyond 6 months.Results did not differ according to age group or gender (Supplementary Table 2).A sensitivity analysis of cases hospitalized for at least 2 days (71% of cases) and their controls (an indicator described as a severity criterion in World Health Organization [WHO] guidelines [26]) yielded similar results (Supplementary Table 3).
The specific incremental effectiveness of the second booster dose compared with the first booster dose, estimated by restricting the analysis to case-control pairs with a first or a second booster dose, that is, 26 332 cases and 206 125 controls (Supplementary Table 4), was 44% (95% CI, 42%-46%) (Table 4).It was 61% (95% CI, 59%-64%) in the first 2 months, 45% (95% CI, 43%-48%) between 2 and 4 months, and 7% (95% CI, 2%-13%) beyond.In this population, 11% had a history of SARS-CoV-2 infection after the first booster dose (3.6% of cases and 12% of controls).The effectiveness of the second booster dose dropped to 2% (95% CI, −18% to 19%) in those with a recent history of infection (Table 4).The effectiveness of hybrid immunity was estimated at 82% (95% CI, 78%-84%) compared with those who did not receive a second booster dose or have a recent history of infection (Supplementary Table 5).Note that we also observed a decrease in the incremental effectiveness of the first booster dose compared with complete primary vaccination (Supplementary Tables 6 and 7).

DISCUSSION
In this matched case-control study including all hospitalizations for COVID-19 in France between June 1, 2022, and October 15, 2022, compared with no vaccination, effectiveness against the risk of hospitalization for COVID-19 was estimated at 45% for complete primary vaccination, 56% for the first booster dose, and 75% for the second booster dose.Effectiveness was the highest in the 2 months after injection (82%), and then decreased to 52% beyond 9 months (mean duration, 10.7 months).Booster doses provided temporarily increased protection compared with primary vaccination, ranging from 69% within the first 2 months to 22% beyond 6 months.Previous infection conferred strong, long-lasting protection against hospitalization for COVID-19, reaching 70%-80% for Omicron sublineage infections and 50%-60% for infections occurring previously.The second booster provided no additional benefit in protection to individuals who became infected after they received a first booster.Effectiveness of hybrid immunity was 82%.
Compared with unvaccinated individuals, the decrease in vaccine effectiveness of the last dose against the risk of hospitalization for COVID-19 (82% within 2 months vs 52% beyond 9 months) was consistent with other studies [27][28][29][30][31][32][33][34].A US study by Adams et al. [30] during the Omicron period (December 26, 2021, to June 30, 2022) estimated an effectiveness of the first booster dose against the risk of hospitalization of 76% (95% CI, 69%-81%) within the first 4 months vs 39% (95% CI, 22%-53%) beyond that time and an effectiveness of the second booster dose of 62% (95% CI, 35%-78%) in the first 4 months.Another US study by Ferdinands et al. [28] between January 17, 2021, and July 12, 2022, estimated the effectiveness of the first booster dose against the risk of hospitalization at 89% (95% CI, 88%-90%) during the first 2 months and 66% (95% CI, 63%-69%) after 4 months.As mentioned by Carabelli et al. [35], the successive mutations of the different COVID-19 variants only weakly affected the T-cell epitopes and the associated immune response, which would be likely to maintain vaccine effectiveness (50% beyond 6 months in our study).Compared with individuals with a primary vaccination for at least 25 weeks, an English study by Kirsebom et al. [36] estimated the effectiveness of a first or second booster dose against the risk of hospitalization at 14 weeks to be ∼60% against the BA.4 and BA.5 variants and ∼20% after 24 weeks.In our study, the incremental benefit of the second booster over the first against the risk of severe disease was 44% (95% CI, 42%-46%), ranging from 61% (95% CI, 59%-64%) in the first 2 months to 7% (95% CI, 2%-13%) beyond 4 months.These estimates are consistent with the results of 2 studies among older adults: A Canadian study [37] conducted in long-term care facilities among individuals aged 60 years or older estimated the effectiveness of the second booster dose compared with the first at 40% (95% CI, 24%-52%); an Italian study [38] among individuals aged 80 years or older estimated the effectiveness of the second booster dose compared with the first at 43% (95% CI, 31%-55%) at 1 month and 27% (95% CI, 8-43%) at 4 months.If our study was not limited to the elderly population, the mean age of cases and controls in this subpopulation was 77 and 78 years, respectively (Supplementary Table 4).Although some studies have shown high and continuous effectiveness of boosters over time against the risk of severe forms of COVID-19 [39][40][41], these studies involved fewer events and a younger population.
We observed a benefit of hybrid immunity conferred by both effectiveness of vaccination and SARS-CoV-2 infection, consistent with several studies that found maximum protection over time with hybrid immunity [42][43][44][45][46][47][48].As in a review by Stein et al. [12], protection of prior infection against a subsequent severe COVID-19 infection appears to last up to >10 months for ancestral variants and even up to 20 months in our study, thus being at least as durable as that provided by 2 doses of vaccination.However, SARS-CoV-2 infection is associated with an increased risk of hospitalization for COVID-19, admission to intensive care, and death, but also, a risk of persistent symptoms, long COVID, and short-and medium-term respiratory, cardiovascular, and neurological complications [49][50][51][52], as opposed to vaccination.In case of a recent infection conferring a high level of protection, the effectiveness of a second booster dose appeared lower, probably because people who did not receive a second booster dose were already substantially protected from hospitalization, almost as well as those who did receive a second booster.In addition, the relatively lower effectiveness of vaccination on Omicron variants could be explained by the immune evasiveness properties of the Omicron variants [35], while a booster dose would allow a broader immune response [30].This study has some limitations.Some SARS-CoV-2 infections are not recorded in the testing database.Some individuals do not want to be tested or have not been tested because of asymptomatic infections, and the results of self-tests are not recorded.This may affect (and probably underestimate) our estimate of hybrid immunity, as individuals in the reference exposure group are probably better protected than actually recorded in our data, and at least partly lead to an artificial decrease in vaccine effectiveness [34,43].Vaccine effectiveness may also have been underestimated due to incidental findings of SARS-CoV-2 during hospital admission screening, leading to misclassification of the outcome of severe disease due to Omicron.However, we only included hospitalized cases with a principal or related diagnosis of COVID-19 (no associated diagnosis).And a sensitivity analysis of cases hospitalized for at least 2 days (71% of cases) and their controls, an indicator described as a severity criterion in the WHO guidelines [26], produced similar results.Hospitalization data were complete from June through September, but completeness was 40% for October at the time of the analyses.However, the number of controls for whom hospitalization was not reported is small compared with the total number of controls; therefore, the risk of biasing the estimates is likely limited.By design, the selected control individuals had a higher risk of hospitalization than the general population.Although this makes the estimates more reliable, they may not be generalizable to individuals at lower risk.Characterization of the BA.4 and BA.5 sublineages was unavailable individually in the databases and therefore relied on the period of predominance defined from surveillance data [53]: as of the beginning of June 2022, the BA.5 variant represents >40% and the BA.4 variant 5% of variants in circulation.In mid-June, the BA.5 variant became a 60% majority, reaching >85% of variants in circulation from early July and until the end of the inclusion period in mid-October.Bivalent vaccines were unavailable over the study period, so our results are not generalizable to these vaccines.Finally, despite the matching of cases and controls on COVID-19 hospitalization risk scores and a relatively balanced distribution of the different adjustment variables (including a large number of risk factors for severe COVID-19), unmeasured residual confounding factors, such as risk behaviors (eg, noncompliance with barrier measures), may remain.
This study focuses on the near-completeness of hospitalizations between June 1 and October 15, 2022, when the BA.4 and BA.5 sublineages of the Omicron variant prevailed.Its originality lies in the matching with controls at equivalent risk of hospitalization and in considering recent episodes of infection when estimating booster effectiveness.

CONCLUSIONS
In the era of Omicron BA.4 and BA.5 predominance, primary vaccination still conferred protection against COVID-19 hospitalization, while booster doses provided additional time-limited protection.The second booster did not provide additional protection in case of infection since the first booster.Further work will be needed to measure protection after bivalent vaccines, which became available in France in October 2022.

Table 3 . Association Between History of SARS-CoV-2 Infection and Hospitalization for COVID-19
Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. a Adjustment for the number of vaccine doses, social deprivation index, tobacco dependence, use of immunosuppressants or oral corticosteroids, history of diabetes, dyslipidemia, hypertension, chronic respiratory disease, and other cancers.

Table 4 . Reduced Risk of Hospitalization for COVID-19 in the Omicron Period Associated With the Second Booster Dose Compared With the First Booster Dose, Overall and Taking Into Account History of Infection Between the First Booster Dose and the Two Months Before the Index Date
Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. a Adjustment for social deprivation index, tobacco dependence, use of immunosuppressants or oral corticosteroids, history of diabetes, dyslipidemia, hypertension, chronic respiratory disease, other cancers, and history of SARS-CoV-2 infection (occurring before the first booster dose).